Leptin-Activated Pathways

Over the past several years we have investigated the central circuits through which leptin acts. We systematically examined distributions of mRNA of leptin receptors in the rat brain by using a probe specific for the long form and a probe recognizing all known forms of the leptin receptor.

We have also assessed the distributions of Fos-like immunoreactivity (Fos-IR) following i.v. leptin administration.

In collaboration with Jeff Flier, MD, laboratory we have investigated the role of leptin to induce the expression of SOCS-3 mRNA. This work has demonstrated that SOCS-3 is an inhibitor of leptin signaling and SOCS-3 mRNA expression is a direct marker of leptin action. We have found that POMC/CART, but not AgRP/NPY, neurons contain leptin-induced Fos-IR. In contrast, both POMC/CART and AgRP/NPY neurons in the arcuate nucleus express leptin-induced SOCS-3 mRNA. Taken together, these results led us to propose the model that POMC cells that express Fos-IR and SOCS mRNA are directly activated by leptin, whereas the AgRP/NPY cells are directly inhibited by leptin.

Leptin, or physiologically relevant falls in leptin, have profound effects on the sympathetic nervous system. Thus, we assessed the distribution of leptin-activated neurons that innervate sympathetic preganglionic neurons in the spinal cord. Our findings suggest that POMC neurons in the hypothalamus that innervate sympathetic preganglionic neurons in the thoracic spinal cord are targets of circulating leptin. The physiological importance of this projection remains to be fully established, but we placed our injections in the regions that provides sympathetic innervation to the heart and brown adipose tissue.

Falls in leptin levels increase both melanin concentrating hormone and orexin mRNAs. Thus, we investigated the functional link between leptin-responsive neurons in the arcuate nucleus and MCH and ORX cells in the lateral hypothalamus. We first assessed the NPY, a-MSH, and AgRP innervation of the LHA, especially the perifornical area. Double-label immunohistochemistry revealed that MCH and ORX neurons receive innervation from NPY, AgRP, and a-MSH immunoreactive fibers.

In a subsequent series of experiments, we investigated the functional significance of the arcuate innervation of MCH and ORX cells. Using retrograde tracing from the perifornical region of the LHA followed by leptin administration, we identified leptin-sensitive neurons in the arcuate nucleus that innervate the LHA. We found retrogradely labeled cells in the ARH containing NPY or POMC mRNA. Following leptin administration, NPY/AgRP cells in the ARH did not express Fos. However, these cells expressed leptin-induced SOCS-3 mRNA. In contrast, leptin induced both Fos-IR and SOCS-3 expression in POMC/CART neurons, many of which also innervated the LHA. These results lead us to hypothesize that leptin directly inhibits NPY/AgRP cells and directly activates POMC/CART neurons that project to the LHA.

Much of the ongoing work in the Elmquist lab is focused on understanding the functional significance of the aforementioned leptin-responsive pathways.